A prospective study of serum metabolites and glioma risk.

Malignant glioma is one of the most lethal adult cancers, yet its etiology remains largely unknown. We conducted a prospective serum metabolomic analysis of glioma based on 64 cases and 64 matched controls selected from Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from collection of baseline fasting serum to diagnosis was nine years (inter-decile range 3-20 years). LC/MS-MS identified 730 known metabolites, and conditional logistic regression models estimated odds ratios for one-standard deviation differences in log-metabolite signals. Forty-three metabolites were associated with glioma at P<0.05. 2-Oxoarginine, cysteine, alpha-ketoglutarate, chenodeoxycholate and argininate yielded the strongest metabolite signals and were inversely related to overall glioma risk (0.0065≤P<0.0083). Also, seven xanthine metabolites related to caffeine metabolism were higher in cases than in controls (0.017≤P<0.042). Findings were mostly similar in high-grade glioma cases, although prominent inversely associated metabolites included the secondary bile acids glycocholenate sulfate and 3β-hydroxy-5-cholenoic acid, xenobiotic methyl 4-hydroxybenzoate sulfate, sex steroid 5alpha-pregnan-3beta, 20beta-diol-monosulfate, and cofactor/vitamin oxalate (0.0091≤P<0.021). A serum metabolomic profile of glioma identified years in advance of clinical diagnoses is characterized by altered signals in arginine/proline, antioxidant, and coffee-related metabolites. The observed pattern provides new potential leads regarding the molecular basis relevant to etiologic or sub-clinical biomarkers for glioma.